Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/10—Spiro-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/10—Laxatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/12—Antidiarrhoeals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/04—Antipruritics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
  • A61P23/02—Local anaesthetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/32—Alcohol-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/36—Opioid-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/10—Antioedematous agents; Diuretics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
  • C07C309/01—Sulfonic acids
  • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
  • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
  • C07C309/01—Sulfonic acids
  • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
  • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C309/06—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing halogen atoms, or nitro or nitroso groups bound to the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/235—Saturated compounds containing more than one carboxyl group
  • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
  • C07C59/255—Tartaric acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/235—Saturated compounds containing more than one carboxyl group
  • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
  • C07C59/265—Citric acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/10—Spiro-condensed systems

Definitions

• the present invention relates to spirocyclic cyclohexane derivatives, processes for their preparation, medicaments containing these compounds and the use of spirocyclic cyclohexane derivatives for the preparation of medicaments.
• the heptadekapeptide nociceptin is an endogenous ligand of the ORL1 (opioid receptor-like) receptor ( Meunier et al., Nature 377, 1995, pp. 532-535 ), which belongs to the family of opioid receptors and is found in many regions of the brain and spinal cord and has a high affinity for the ORL1 receptor.
• ORL1 opioid receptor-like receptor
• the ORL1 receptor is homologous to the ⁇ , ⁇ and ⁇ opioid receptors and the amino acid sequence of the nociceptin peptide is very similar to those of the known opioid peptides.
• the activation of the receptor induced by the nociceptin leads to an inhibition of the adenylate cyclase via the coupling with G i / o proteins ( Meunier et al., Nature 377, 1995, pp. 532-535 ).
• the nociceptin peptide exhibits pronociceptive and hyperalgesic activity in various animal models after intercerebroventular administration ( Reinscheid et al., Science 270, 1995, pp. 792-794 ). These findings can be explained as an inhibition of stress-induced analgesia ( Mogil et al., Neuroscience 75, 1996, pp. 333-337 ). An anxiolytic activity of nociceptin was also demonstrated in this context ( Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858 ).
• nociceptin has an antinociceptive effect in various pain models, for example in the mouse tail flick test ( King et al., Neurosci. Lett., 223, 1997, 113-116 .
• an antinociceptive effect of nociceptin was detected, which is particularly so far interesting is that the efficacy of nociceptin increases after axillary spinal nerve axotomy. This is in contrast to the classical opioids, whose effectiveness decreases under these conditions ( Abdulla and Smith, J. Neurosci., 18, 1998, pp. 9685-9694 ).
• the ORL1 receptor is also involved in the regulation of other physiological and pathophysiological processes. These include, inter alia, learning and memory formation ( Manabe et al., Nature, 394, 1997, pp. 577-581 ), Hearing ( Nishi et al., EMBO J., 16, 1997, pp. 1858-1864 ) as well as numerous other processes.
• learning and memory formation Manabe et al., Nature, 394, 1997, pp. 577-581
• Hearing Nishi et al., EMBO J., 16, 1997, pp. 1858-1864
• numerous other processes include, inter alia, learning and memory formation ( Manabe et al., Nature, 394, 1997, pp. 577-581 ), Hearing ( Nishi et al., EMBO J., 16, 1997, pp. 1858-1864 ) as well as numerous other processes.
• Calo et al. (Br. J. Pharmacol., 129, 2000, 1261-1283
• analgesia stimulation and Regulation of food intake, influence on ⁇ -agonists such as morphine, treatment of withdrawal symptoms, reduction of addictive potential of opioids, anxiolysis, modulation of locomotor activity, memory disorders, epilepsy; Modulation of neurotransmitter release, in particular of glutamate, serotonin and dopamine, and thus neurodegenerative diseases; Influence of the cardiovascular system, induction of an erection, diuresis, antinatriuresis, electrolyte balance, arterial blood pressure, water retention diseases, intestinal motility (diarrhea), respiratory relaxant effects, micturition reflex (urinary incontinence). Furthermore, the use of agonists and antagonists as anoretic agents, analgesics (also in co-administration with opioids) or nootropics is discussed.
• opioid receptors such as the ⁇ receptor, but also the other subtypes of these opioid receptors, namely ⁇ and ⁇ , play a major role in the field of pain therapy as well as other indications. Accordingly, it is favorable if the compound also show activity on these opioid receptors.
• EP 0466548 discloses spirocyclic 1,2,3,4-tetrahydro- ⁇ -carboline derivatives which, however, carry no amino group on the spirocyclic saturated ring. These compounds have an analgesic effect.
• the object of the present invention was to provide medicaments which act on the nociceptin / ORL1 receptor system and thus for medicaments, in particular for the treatment of the various diseases associated with this prior art system or for use in patients the indications mentioned there are suitable.
• R 1 and R 2 are independently H, C 1-5 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted, or CHO; or the radicals R 1 and R 2 together represent CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 11 CH 2 CH 2 or (CH 2 ) 3-6 ; in which
• R 11 H or C 1-5 alkyl, in each case saturated or unsaturated, branched or unbranched, unsubstituted;
• R 3 is C 1-5 -alkyl, in each case saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C 3-8 - (hetero) cycloalkyl, in each case saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; Aryl, in each case unsubstituted or monosubstituted or polysubstituted; or via C 1-3 -alkyl, in each case saturated or unsaturated, branched or unbranched, bound aryl or C 3-8 (hetero) cycloalkyl, in each case unsubstituted or monosubstituted or polysubstituted; W is NR 4 , O or S; in which R 4 for H; C 1-5 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstitute
• R 12 H C 1-5 -alkyl, in each case saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C 3-8 - (hetero) cycloalkyl, in each case saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; or via C 1-3 -alkyl, in each case saturated or unsaturated, branched or unbranched, bound aryl, C 3-8 - (hetero) -cycloalkyl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; OR 13 ; or NR 14 R 15 ;
• C 1-5 alkyl is in each case saturated or unsaturated, branched or unbranched, unsubstituted; or C 3-8 - (hetero) cycloalkyl, each saturated or unsaturated, unsubstituted;
• R 14 and R 15 are independently H; or C 1-5 alkyl, in each case saturated or unsaturated, branched or unbranched, unsubstituted; or R 14 and R 15 together form CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 16 CH 2 CH 2 or (CH 2 ) 3-6 , where R 16 is H; or C 1-5 -alkyl saturated or unsaturated, branched or unbranched, unsubstituted; X is O, S, SO, SO 2 or NR 17 ; in which
• R 17 is H; C 1-5 alkyl, saturated or unsaturated, branched or unbranched; COR 12 or SO 2 R 12 ; wherein in the radicals R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 in the context of "alkyl" by the term “substituted” the substitution of one or more hydrogen radicals by F, Cl, Br, I, -CN, NH 2 , NH-alkyl, NH- (hetero) cycloalkyl, NH-alkyl-OH , N (alkyl) 2 , N ((hetero) cycloalkyl) 2 , N (alkyl-OH) 2 , NO 2 , SH, S-alkyl, S- (hetero) -cycloalkyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl, O- (hetero) cycloalkyl, O-
• R 7 , R 8 , R 9 and R 10 When summarizing various radicals, for example R 7 , R 8 , R 9 and R 10 and the summary of radicals on their substituents, such as.
• OR 13 , SR 13 , SO 2 R 13 or COOR 13 a substituent, for example R 13 , for two or more radicals, for example R 7 , R 8 , R 9 and R 10 , assume different meanings within a substance.
• the compounds of the invention show good binding to the ORL1 receptor, but also to other opioid receptors.
• C 1-5 -alkyl and “C 1-3 -alkyl” for the purposes of this invention include acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight-chain, having 1, 2, 3, 4 or 5 C Atoms or 1, 2 or 3 C-atoms, ie C 1-5 -alkanylyl, C 2-5 -alkenyls and C 2-5 -alkynyls or C 1-3 -alkanyles, C 2-3 -alkenyls and C 2-3 alkynyls.
• Alkenyls have at least one CC double bond and alkynyls at least one CC triple bond.
• (hetero) cycloalkyl or "C 3-8 (hetero) cycloalkyl” for the purposes of this invention means cyclic hydrocarbons having 3, 4, 5, 6, 7 or 8 carbon atoms wherein the hydrocarbons are saturated or unsaturated (but not aromatic), can be.
• (hetero) cycloalkyl the term also includes saturated or unsaturated (but not aromatic) (hetero) cycloalkyl in which one or two carbon atoms are replaced by a heteroatom S, N or O.
• C 3-8 - (hetero) cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, but also tetrahydropyranyl, dioxanyl, dioxolanyl, morpholinyl, piperidinyl, Piperazinyl, pyrazolinonyl and pyrrolidinyl contains.
• (CH 2 ) 3-6 is -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 - and CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - to understand.
• aryl in the context of this invention means carbocyclic ring systems having at least one aromatic ring, but without heteroatoms in only one of
• aryl radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems. Particularly advantageous are phenyl or naphthyl radicals.
• heteroaryl represents a 5-, 6- or 7-membered cyclic aromatic radical containing at least 1, optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are the same or different.
• the heterocycle may also be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulfur.
• the heteroaryl radical is selected from the group consisting of pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl, phthalazinyl, pyrazolyl, imidazolyl, Thiazolyl, oxazolyl, isoxazoyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl or oxadiazolyl, wherein the bond to the compounds of general structure
• -Oalkyl also includes -O-CH 2 -CH 2 -O-CH 2 -CH 2 -OH.
• aryl In the context of this invention, "aryl”, “heteroaryl” and “cycloalkyl” are understood as meaning “monosubstituted or polysubstituted” the one or more, for example two, three, four or five times, substitution of one or more hydrogen atoms of the ring system by F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH- (hetero) cycloalkyl), NH -Alkyl-OH, N (alkyl) 2 , N (alkyl-aryl) 2 , N (alkyl-heteroaryl) 2 , N ((hetero) cycloalkyl)) 2 , N (alkyl-OH) 2 , NO 2 , SH , S-alkyl, S- (hetero) cycl
• salt means any form of the active ingredient according to the invention in which it assumes an ionic form or is charged and is coupled with a counterion (a cation or anion) or is in solution.
• a counterion a cation or anion
• salts of the active ingredient with other molecules and ions in particular complexes that are complexed via ionic interactions.
• they include (and this is also a preferred embodiment of this invention) physiologically acceptable salts, especially physiologically acceptable salts with cations or bases and physiologically acceptable salts with anions or acids or else a salt formed with a physiologically acceptable acid or a physiologically acceptable cation ,
• physiologically acceptable salt with anions or acids is understood as meaning salts of at least one of the compounds according to the invention-usually, for example, nitrogen-protonated-as a cation having at least one anion which is physiologically-in particular when used in humans and / or Mammal - are compatible.
• a physiologically acceptable acid namely salts of the respective active ingredient with inorganic or organic acids, which are physiologically compatible - in particular when used in humans and / or mammals.
• physiologically acceptable salts of certain acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethylsebacic acid, 5-oxo-proline , Hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, ⁇ -lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid.
• Particularly preferred is the hydrochloride salt, citrate and hemicitrate.
• the term salt formed with a physiologically acceptable acid means salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals.
• the hydrochloride and the citrate are especially preferred.
• physiologically acceptable acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid , Nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid.
• physiologically compatible salt with cations or bases refers to salts of at least one of the compounds according to the invention-usually a (deprotonated) acid-as an anion having at least one, preferably inorganic, cation which is physiologically-in particular when used in humans and / or mammalian.
• Particularly preferred are the salts of the alkali and alkaline earth metals but also ammonium salts, but especially (mono-) or (di) sodium, (mono-) or (di) potassium, magnesium or calcium salts.
• the term salt formed with a physiologically compatible cation means salts of at least one of the respective compounds as anion with at least one inorganic cation which is physiologically acceptable, in particular when used in humans and / or mammals.
• Particularly preferred are the salts of the alkali and alkaline earth metals but also ammonium salts, but especially (mono-) or (di) sodium, (mono-) or (di) potassium, magnesium or calcium salts.
• R 1 and R 2 independently of one another are H, C 1-5 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted, or CHO,
• R 3 represents phenyl, benzyl or phenethyl, in each case unsubstituted or monosubstituted or polysubstituted on the ring
• R 5 is H, C 1-5 alkyl, branched or unbranched, substituted or monosubstituted or polysubstituted, COOR 13
• R 6 is H or C 1-5 -alkyl
• R 7 , R 8 , R 9 and R 10 are independently H; C 1-5 -alkyl, branched or unbranched, unsubstituted or monosubstituted or polysubstituted; F, Cl, Br, I, OH, OCH 3 , NH 2 , COOH, COOCH 3 , NHCH 3 , N (CH 3 ) 2 , NO 2 , SO 3 H, SO 2 NH 2 , pyridyl or phenyl.
• W is NR 4 , O or S and X is O, S, SO, SO 2 or NR 17 ,
• R 1 and R 2 are independently H; C 1-4 alkyl, branched or unbranched, unsubstituted; or CHO stands
• R 4 for H; C 1-3 alkyl, mono- or polysubstituted or unsubstituted; and or
• R 5 and R 6 are each H and / or
• R 7 , R 8 , R 9 and R 10 are independently H; C 1-5 -alkyl, OC 1-3 -alkyl, in each case branched or unbranched, saturated or unsaturated, unsubstituted or monosubstituted or polysubstituted; F, Cl, Br, I, CF 3, OH, SH, SCH 3, OCH 3, NH 2, COOH, COOCH 3, NHCH 3, N (CH 3) 2, NO 2, SO 3 H, SO 2 NH 2 Pyridyl or phenyl, wherein compounds in which W is NR 4 and X is O, NH or NCOR 12 are particularly preferred.
• R 1 and R 2 are independently H or CH 3 , wherein R 1 and R 2 are not H at the same time.
• R 3 is phenyl, benzyl or phenethyl, in each case unsubstituted or monosubstituted or polysubstituted on the ring; means especially
• R 3 is phenyl, benzyl, phenethyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl; 3-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- Methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,
• the radical R 5 is H, CH 3 , COOH, COOCH 3 or CH 2 OH is the radical R 6 is H.
• R 7 R 8 , R 9 and R 10 are independently H; C 1-5 -alkyl, branched or unbranched, unsubstituted or monosubstituted or polysubstituted; F, Cl, Br, I, CF 3 , OH, OCH 3 , NH 2 , COOH, COOCH 3 , NHCH 3 , N (CH 3 ) 2 , NO 2 , SO 3 H, SO 2 NH 2 , pyridyl or phenyl preferably the radicals R 7 R 8 , R 9 and R 10 for H or one of R 7 , R 8 , R 9 and R 10 is H; C 1-5 -alkyl, branched or unbranched, unsubstituted or monosubstituted or polysubstituted, in particular methyl; and F, Cl, Br, I, OH, OCH 3, COOH, COOCH 3, NH 2, NHCH 3, N (CH 3) 2, NO 2, SO 3 H, SO 2 NH
• W is NR 4 , wherein R 4 is H, CH 3 , C 2 H 5 , phenyl, and X is O, NH, or NCOR 12 .
• R 1 and R 2 independently of one another are H or CH 3 , in particular CH 3 , R 3 is phenyl.
• the substances according to the invention act, for example, on the ORL1 receptor relevant in connection with various diseases, so that they are suitable as pharmaceutical active substance in a pharmaceutical.
• Another object of the invention are therefore medicaments containing at least one inventive spirocyclic cyclohexane derivative, and optionally suitable additives and / or auxiliaries and / or optionally other active ingredients.
• the medicaments according to the invention optionally contain suitable additives and / or adjuvants, such as carrier materials, fillers, solvents, diluents, dyes and / or binders and can be used as liquid dosage forms in the form of injection solutions, drops or juices, as semi-solid Dosage forms in the form of granules, tablets, pellets, patches, capsules, patches / spray patches or aerosols. The choice of excipients etc.
• the amounts to be used depend on whether the drug is administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example on the skin, mucous membranes or in the mouth the eyes, to be applied.
• preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable, for parenteral, topical and inhalative administration solutions, suspensions, readily reconstitutable dry preparations and sprays.
• Spirocyclic cyclohexane derivatives according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of skin penetration promoting agents, are suitable percutaneous administration preparations. Orally or percutaneously applicable preparation forms can release the spirocyclic cyclohexane derivatives according to the invention with a delay.
• the spirocyclic cyclohexane derivatives of the invention can also be used in parenteral long-term depot forms such. As implants or implanted pumps are applied. In principle, other active compounds known to the person skilled in the art may be added to the medicaments according to the invention.
• the amount of drug to be administered to the patient varies depending on the weight of the patient, the mode of administration, the indication and the severity of the disease. Usually 0.00005 to 50 mg / kg, preferably 0.001 to 0.5 mg / kg of at least one spirocyclic cyclohexane derivative according to the invention are applied.
• the medicament contains, in addition to at least one spirocyclic cyclohexane derivative, another active substance, in particular an opioid, preferably a strong opioid, in particular morphine, or an anesthetic, preferably hexobarbital or halothane.
• another active substance in particular an opioid, preferably a strong opioid, in particular morphine, or an anesthetic, preferably hexobarbital or halothane.
• a contained spirocyclic cyclohexane derivative according to the invention is present as a pure diastereomer and / or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and / or enantiomers.
• spirocyclic cyclohexane derivatives of the present invention may be used for the manufacture of a medicament for the treatment of pain, especially acute, neuropathic or chronic pain.
• Another object of the invention is therefore the use of a spirocyclic cyclohexane derivative of the invention for the manufacture of a medicament for the treatment of pain, in particular of acute, visceral, neuropathic or chronic pain.
• Another object of the invention is the use of a spirocyclic cyclohexane derivative of the invention for the manufacture of a medicament for the treatment of anxiety, stress and stress related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunction, learning and memory disorders.
• a used spirocyclic cyclohexane derivative as a pure diastereomer and / or Enantiomer is present as a racemate or as a non-equimolar or equimolar mixture of diastereomers and / or enantiomers.
• Another object of the invention is a method for the treatment, in particular in one of the aforementioned indications, of a non-human mammal or human, which or a treatment of pain, especially chronic pain, requires, by administering a therapeutically significant dose of a spirocyclic cyclohexane derivative of the invention , or a medicament according to the invention.
• Another object of the invention is a process for preparing the spirocyclic cyclohexane derivatives of the invention as set forth in the following description and examples.
• a process for preparing a spirocyclic cyclohexane derivative according to the invention which is mentioned in the following main process, is particularly suitable, with the following steps, where X, W, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 have the meaning given for compounds according to the invention of formula I, and R 01 and R 02 have the meaning given for compounds according to the invention of formula I for R 1 and R 2 and, in addition, independently of one another may represent a protective group:
• Spirocyclic cyclohexane derivatives of the general formula I in which X is SO or SO 2 can be obtained by reacting spirocyclic cyclohexane derivatives of the general formula I in which X is S with an oxidizing agent, for example H 2 O 2 .
• ether means diethyl ether, "EE” ethyl acetate and “DCM” dichloromethane.
• equivalents means equivalent molar amounts, "m.p.” Melting point or melting range, “Zers.” Decomposition, "RT” room temperature, “abs.” absolute (anhydrous),, “rac.” racemic, “conc.” concentrated, “min” minutes, “h” hours, “d” days, “vol.%” volume percent, “m%” mass percent and “M” is a concentration in mol / l.
• the stationary phase used for the column chromatography was silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt.
• reaction mixture was treated with 1 M NaOH (30 ml) and stirred for 30 min.
• the organic phase was separated and the remaining aqueous phase extracted with DCM (2 ⁇ 30 ml).
• the combined organic phases were washed with 1 M NaOH (1 x 30 mL) and water (2 x 30 mL) and dried over sodium sulfate. After distilling off the solvent, a yellow solid was obtained, which was washed with EA.
• the substantially solid residue obtained after distilling off the solvent was added with methanol (20 ml), warmed and stirred for 15 hours.
• the suspended solid is the less polar diastereoisomer.
• the more polar product was in the methanolic solution.
• the less polar diastereoisomer was obtained in a yield of 571 mg with a mp of 284-286 ° C.
• Example 1 studies on cardiovascular compatibility were carried out. It was found that Example 1 compared to the two clinically used opioids fentanyl and sufentanil has advantages in terms of cardiovascular compatibility.
• the more apolar diastereoisomer of 1,1- (3-dimethylamino-3-phenylpentamethylene) -1,3,4,9-tetrahydropyrano [3,4-b] indole (1.2 g, 3.33 mmol ) was dissolved in hot ethanol (350 ml) and treated with an equally hot solution of citric acid (1.2 g, 6.25 mmol) in ethanol (30 ml). After cooling, the mixture was left for 4 h at about 10 ° C. The resulting solid was filtered off with suction. The hemicitrate could thus be obtained in a yield of 1.05 g as a white solid with a mp of 259-265 ° C.
• the diastereoisomer mixture obtained according to method A (172 mg, 0.457 mmol) was dissolved in hot ethanol (130 ml), combined with citric acid (88.6 mg, 0.461 mmol) and stirred at 65 ° C. for 10 min. After cooling to RT, the mixture was stirred for 20 h. The resulting solid was filtered off with suction, washed with cold ethanol (2 ⁇ 0.5 ml) and then dried. There was obtained 85 mg of the hemicitrate of the non-polar diastereoisomer of 1,1- (3-dimethylamino-3-phenyl-pentamethylene) -1,3,4,9-tetrahydro-2-thia-9-azafluorene (m.p. 241-243 ° C).
• the ethanolic mother liquor obtained according to Example 4 was reduced to 25 ml of solution, admixed with 20 ml of Et 2 O and stirred at RT for 1 h.
• the precipitate was filtered off with suction, washed with Et 2 O (3 ⁇ 2 ml) and dried (62 mg, mp 165-169 ° C., mixture of diastereoisomers).
• a further white solid was obtained by adding a further 50 ml of diethyl ether. This was also filtered off with suction, washed with Et 2 O (3 ⁇ 2 ml) and dried.
• 1,1- (3-dimethylamino-3-phenylpentamethylen) (50 mL) -3,4-dihydro-1 H -2-oxa-9-thiafluoren (110 mg, 0.29 mmol) was dissolved in hot ethanol and treated with a 0.1 M solution of L-tartaric acid (3.2 mL, 0.32 mmol) in ethanol. After cooling to RT, the reaction was stirred for 24 h. After 24 h, the solvent was concentrated to a residual volume of about 10 ml. The now precipitated Fesfsfoff was filtered off with suction at RT, washed with ethanol (3 ⁇ 1 ml) and dried.
• the resulting crude product (600 mg, 1.66 mmol) was dissolved in hot ethanol (100 mL) and treated with an equally hot solution of citric acid (600 mg, 3.12 mmol) in ethanol (20 mL). After cooling to about 5 ° C, a solid precipitated, which was sucked off after standing for 2 hours.
• the hemicitrate of 1,1- (3-dimethylamino-3-phenylpentamethylene) -3,4-dihydro-1 H -2,9-dioxafluorene was thus obtained in a yield of 626 mg as a white solid (m.p .: 201-202 ° C ) receive.
• This aqueous phase was adjusted to pH 11 with NaOH (5 mol / L) and extracted with EA (3 ⁇ 30 mL). The organic phase was dried with sodium sulfate and concentrated.
• the product was a mixture of the two diastereoisomeric 1,1- (3-dimethylamino-3-phenylpentamethylene) -3,4-dihydro-1 H -2,9-diazafluorenes, which could be separated by chromatography on silica gel with methanol. The less polar product was obtained in a yield of 557 mg (31%) as a white solid.
• Example 13 1,1- (3-Dimethylamino-3-phenyl-pentamethylene) -6-methoxy-1,3,4,9-tetrahydropyrano [3,4-b] indole hydrochloride
• reaction mixture was treated with 1 M NaOH (30 ml) and stirred for 30 min.
• the organic phase was separated and the remaining aqueous phase extracted with DCM (2 ⁇ 30 ml).
• the combined organic phases were washed with water (2 ⁇ 30 ml) and dried over sodium sulfate.
• the largely solid residue obtained after distilling off the solvent was treated with methanol (70 ml), stirred for 2 h and the resulting suspension was filtered.
• Example 14 1,1- (3-Dimethylamino-3-phenylpentamethylene) -3-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole hemicitrate, nonpolar diastereoisomer
• reaction mixture was treated with 1M NaOH (20 ml) and stirred for 30 min.
• the organic phase was separated and the remaining aqueous solution extracted with DCM (2 ⁇ 30 ml).
• the combined organic phases were washed with water (2 ⁇ 30 ml) and dried over sodium sulfate.
• the obtained after distilling off the solvent largely solid residue was washed with Added methanol (70 ml) and stirred for 2 h.
• the residue consisted mainly of the more polar diastereoisomer, which could be obtained in a yield of 260 mg as a white solid.
• these 260 mg, 0.69 mmol were suspended in hot ethanol (20 ml) and treated with an equally hot solution of citric acid (133 mg, 0.69 mmol) in ethanol (5 ml). The substance was completely dissolved and did not precipitate on cooling to about 5 ° C.
• Example 16 6-Bromo-1,1- (3-dimethylamino-3-phenylpentamethylene) -3-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole hemicitrate
• reaction mixture was treated with 1 M NaOH (30 ml) and stirred for 30 min.
• the organic phase was separated and the remaining aqueous solution extracted with DCM (2 ⁇ 30 ml).
• the combined organic extracts were washed with water (2 x 30 ml) and dried over sodium sulfate.
• the substantially solid residue obtained after distilling off the solvent was added with methanol (70 ml) and stirred for 1 h. The material that had not dissolved was filtered off with suction.
• Example 17 1,1- (3-Dimethylamino-3-phenylpentamethylene) -3-methyl-6-nitro-1,3,4,9-tetrahydropyrano [3,4-b] indole citrate, nonpolar diastereoisomer
• reaction mixture was admixed with 1M NaOH (50 ml) and DCM (20 ml) and stirred for 30 min.
• the organic phase was separated and the remaining aqueous solution extracted with DCM (3 ⁇ 40 ml).
• the combined organic phases were washed with water (2 ⁇ 30 ml) and dried over sodium sulfate.
• the glassy residue obtained after distilling off the solvent was added with methanol (30 ml) and stirred for 1 hour.
• the insoluble in methanol solid proved to be a mixture of diastereoisomers.
• EA silica gel
• the less polar product was obtained in a yield of 154 mg as a white solid with a mp. Of 252-265 ° C in pure form. 134 mg of this was dissolved in hot ethanol (150 ml) and treated with an equally hot solution of citric acid (110 mg, 0.57 mmol) in ethanol (20 ml). The batch was cooled and left at about 10 ° C for 20 h. The resulting solid was filtered off with suction.
• Example 18 1,1- (3-Dimethylamino-3-phenylpentamethylene) -3-methyl-6-nitro-1,3,4,9-tetrahydropyrano [3,4-b] indole citrate, more polar diastereoisomer
• Example 17 also 120 mg of the more polar diastereoisomer of 1,1- (3-dimethylamino-3-phenylpentamethylene) -3-methyl-6-nitro-1,3,4,9-tetrahydropyrano [3,4-b ] indole with a mp. Of 230-240 ° C. This 120 mg was dissolved in hot ethanol (120 ml) and treated with an equally hot solution of citric acid (100 mg, 0.52 mmol) in ethanol (10 ml). The solution was cooled and concentrated to dryness in vacuo. The resulting residue was taken up in water (10 ml) to give the citrate as a crystalline solid.
• reaction mixture was treated with 1 M NaOH (30 ml) and stirred for 30 min.
• the organic phase was separated and the remaining aqueous solution extracted with DCM (2 ⁇ 30 ml).
• the combined organic phases were washed with water (2 ⁇ 30 ml) and dried over sodium sulfate.
• the oily residue obtained after distilling off the solvent was added with methanol (50 ml) and stirred for 1 hour. There was a suspension.
• Example 20 6-Chloro-1,1- (3-dimethylamino-3-phenylpentamethylene) -3-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole citrate, more polar diastereoisomer
• the product consisted almost exclusively of the more polar diastereoisomer of 6-chloro-1,1- (3-dimethylamino-3-phenylpentamethylene) -3-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole ( 390 mg yellow solid). These 390 mg were suspended in hot ethanol (20 ml) and added with an equally hot solution of citric acid (385 mg, 2 mmol) in ethanol (10 ml).
• Example 22 1,1- (3-Dimethylamino-3- (4-fluorophenyl) pentamethylene) -1,3,4,9-tetrahydropyrano [3,4-b] indole hemicitrate
• Example 23 1,1- (3-Dimethylamino-3- (3-fluorophenyl) pentamethylene) -1,3,4,9-tetrahydropyrano [3,4-b] indole hemicitrate
• Example 25 1,1- (3-Dimethylamino-3-phenylpentamethylene) -6-fluoro-1,3,4,9-tetrahydropyrano [3,4-b] indole hemicitrate, more polar diastereoisomer
• Example 26 1,1- (3-Dimethylamino-3-phenylpentamethylene) -6-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole hemicitrate
• Example 27 1,1- (3-Dimethylamino-3-phenyl-pentamethylene) -9-phenyl-1,3,4,9-tetrahydropyrano [3,4-b] indole citrate
• Example 28 1,1- (3-Methylamino-3-phenylpentamethylene) -1,3,4,9-tetrahydropyrano [3,4-b] indole hemicitrate
• the reaction was diluted with water (30 ml), adjusted to pH 11 with NaOH (5 mol / l) and extracted with 1,2-dichloroethane (3 ⁇ 30 ml). The organic phase was dried with sodium sulfate and concentrated. The brown solid residue was recrystallized from methanol. There was obtained 236 mg of a white solid. 100 mg of this was dissolved in hot ethanol (10 ml) and treated with an equally hot solution of citric acid (62 mg, 0.32 mmol) in ethanol (1 ml). After cooling to about 5 ° C, the approach was allowed to stand for 4 h. The resulting solid was filtered off with suction.
• Example 32 2-acetyl-1,1- (3-dimethylamino-3-phenylpentamethylen) -7-fluoro-3,4-dihydro-1 H -2,9-diazafluorene citrate, more non-polar diastereoisomer
• Example 33 1,1- (3-dimethylamino-3-phenylpentamethylen) -3-methyl-3,4-dihydro-1 H -2,9-diazafluorene citrate
• the batch was diluted with water (20 ml), adjusted to pH 11 with NaOH (5 mol / l) and extracted with 1,2-dichloroethane (3 x 20 ml). The organic phase was dried with sodium sulfate and concentrated. The residue was a contaminated mixture of the two diastereoisomeric 1,1- (3-dimethylamino-3-phenylpentamethylene) -3-methyl-3,4-dihydro-1 H -2,9-diazafluorenes which were purified by recrystallization from methanol, but could not be separated (660 mg of white solid).
• reaction was diluted with water (40 ml), adjusted to pH 11 with NaOH (5 mol / l) and extracted with 1,2-dichloroethane (3 ⁇ 25 ml). The combined organic phases were dried with sodium sulfate and concentrated.
• Example 35 1,1- (3-Dimethylamino-3-phenylpentamethylene) -6-fluoro-3-methyl-1,3,4,9-tetrahydropyrano [3,4-b] indole hemicitrate
• Example 36 3,6-Dimethyl-1,1- (3-dimethylamino-3-phenylpentamethylene) -1,3,4,9-tetrahydropyrano [3,4-b] indole hemicitrate, nonpolar diastereoisomer
• Example 38 1,1- (3-Dimethylamino-3-phenyl-pentamethylene) -3-methyl-9-phenyl-1,3,4,9-tetrahydropyrano [3,4-b] indole citrate
• Example 39 1,1- (3-Dimethylamino-3- (4-fluorophenyl) pentamethylene) -1,3,4,9-tetrahydro-2-thia-9-azafluorene Methanesulfonate
• the precipitated methanesulfonate was filtered off with suction, washed with DCM (3 ⁇ 1 ml) and diethyl ether (3 ⁇ 3 ml).
• the methanesulfonate of one of the two possible diastereoisomers of 1,1- (3-dimethylamino-3- (4-fluorophenyl) pentamethylene) -1,3,4,9-tetrahydro-2-thia-9-azafluorene was obtained in a yield of 550 mg as a white solid (mp 245-250 ° C).
• Example 40 1,1- (3-Dimethylamino-3- (3-fluorophenyl) pentamethylene) -1,3,4,9-tetrahydro-2-thia-9-azafluorene Methanesulfonate
• Example 41 1,1- (3-Dimethylamino-3-phenylpentamethylene) -3,4-dihydro-1H-9-oxa-2-thiafluorene citrate
• Example 44 1,1- (3-Dimethylamino-3-phenylpentamethylene) -6-bromo-1,3,4,9-tetrahydropyrano [3,4-b] indole hemicitrate
• Example 45 1,1- (3-Dimethylamino-3-phenylpentamethylene) -1,3,4,9-tetrahydropyrano [3,4-b] indole-6-ol citrate
• Example 46 (3 S) -1,1- (3-dimethylamino-3-phenylpentamethylen) -3,4-dihydro-3-methoxycarbonyl-1 H -2,9-diazafluorene citrate
• the batch was diluted with water (20 ml) and adjusted to pH 11 with NaOH (5 mol / l).
• EA 20 mL
• a white solid precipitated, which was suctioned off.
• the solid was washed with water (3 x 5 mL) and dried.
• This 600 mg was dissolved in hot ethanol (30 ml) and treated with an equally hot solution of citric acid (276 mg, 1.44 mmol) in ethanol (5 ml). After cooling to about 5 ° C, the approach was allowed to stand for 4 h.
• the resulting solid was filtered off with suction.
• the citrate of (3 S) -1,1- (3-dimethylamino-3-phenylpentamethylen) -3,4-dihydro-3-methoxycarbonyl-1 H -2,9-diazafluorene was so than about 70:30 mixture of less polar and more polar diastereoisomer are obtained in a yield of 875 mg (white solid, mp 193-196 ° C).
• the batch was diluted with water (20 ml) and adjusted to pH 11 with NaOH (5 mol / l).
• EA 20 mL
• a white solid precipitated, which was suctioned off.
• the solid was washed with water (3 x 5 mL) and dried. It was a mixture of the diastereoisomers of the target product (30% nonpolar: 70% polar), which could be obtained as a white solid with a yield of 700 mg.
• This 700 mg was dissolved in hot ethanol (40 ml) and treated with an equally hot solution of citric acid (346 mg, 1.8 mmol) in ethanol (5 ml). After cooling to about 5 ° C, the approach was allowed to stand for 4 h.
• Example 48 1,1- (3-dimethylamino-3-phenylethyl-pentamethylene) -3,4-dihydro-1H-2,9-diazafluorene
• the solid was washed with water (3 x 25 ml) and over sodium sulfate dried. It was a mixture of the diastereoisomers of the target product (10% nonpolar: 90% polar), which was obtained as a white solid (mp 225-230 ° C) in 4.42 g yield.
• Example 49 1,1- (3-Methylamino-3-phenylpentamethylene) -6-fluoro-1,3,4,9-tetrahydropyrano [3,4-b] indole hemicitrate
• Example 50 1,1- (3-Dimethylamino-3- (4-fluorophenyl) pentamethylene) -3,4-dihydro-1H-2,9-dithiafluorene Methanesulfonate
• Example 51 1,1- (3-Dimethylamino-3-phenylpentamethylene) -3,4-dihydro-1H-2,9-dithiafluorene citrate
• One of the two possible free bases of the target product (335 mg, beige, 57%) was thus obtained with a mp of 210-214 ° C. 120 mg thereof was dissolved in hot ethanol (40 ml), added with citric acid (59.2 mg, 0.308 mmol, dissolved in 1 ml of ethanol) and stirred at 65 ° C for 10 min. After cooling to RT, the reaction was stirred for 20 h. Since no precipitate had precipitated, ethanol was concentrated to 2 ml and diethyl ether (30 ml) was added slowly. The resulting solid was filtered off with suction, with Diethyl ether (3 ⁇ 2 ml) and then dried.
• Example 52 1,1- (3-Dimethylamino-3-phenylpentamethylene) -2-oxo-1,3,4,9-tetrahydro-2-thia-9-azafluorene citrate
• 1,1- (3-Dimethylamino-3-phenylpentamethylene) -3,4-dihydro-1H-2,9-dithiafluorene (200mg, 0.53mmol) was suspended in glacial acetic acid (3ml), stirring 30% , Hydrogen peroxide (200 ul) added dropwise and stirred for 2 h at RT.
• the reaction mixture was mixed with 5 ml of water and made alkaline with 5M NaOH. This resulted in a suspension which did not dissolve completely even after the addition of EA (50 ml).
• the precipitate was filtered off with suction, washed with water (2 ⁇ 1 ml) and discarded.
• the aqueous mother liquor was adjusted to pH 11 with 5M NaOH. This resulted in a white precipitate.
• the solid was filtered off with suction, washed with water (1 ⁇ 2 ml) and ether (3 ⁇ 1 ml) and dried. There were obtained 76 mg of 1,1- (3-dimethylamino-3-phenytpentamethylene) -2-oxo-1,3,4,9-tetrahydro-2-thia-9-azafluorene (mp 188-192 ° C). 61 mg, of which were dissolved in hot ethanol (8 ml), treated with citric acid (32.8 mg, 0.17 mmol) and stirred at 65 ° C for 10 min.
• Tryptophol (4.83 g, 30 mmol) was initially charged in dry THF (80 ml) and initially treated at RT with hexamethyldisilazane (30 ml, 141 mmol) and then with chlorotrimethylsilane (8 ml, 62.6 mmol). The batch was stirred at RT for 20 h.
• the THF was distilled off and the residue was added to the basic reaction with saturated sodium bicarbonate solution.
• the aqueous solution was extracted with ether.
• the organic phase was washed with water and dried over sodium sulfate. After removal of the solvent, the trimethylsilyl ether was obtained in a yield of 6.99 g as a crystalline solid (mp. 47-48 ° C).
• Triphenylphosphandibromide (5.52 g, 14.4 mmol) was dissolved in abs. Acetonitrile (15 ml) under argon, brought to 19 ° C. in a water bath and treated with 2- (benzofuran-3-yl) ethanol (2.11 g, 13.1 mmol) in abs. Acetonitrile (7 ml). During the addition, the temperature of the reaction mixture was maintained between 19 and 21 ° C. The mixture was then allowed to stand for 12 h without further cooling. The reaction mixture was filtered, the resulting filtrate was concentrated. The resulting residue was taken up in cyclohexane (20 ml) and filtered through a 3 cm thick silica gel layer (15 g).
• the aqueous residue was extracted with diethyl ether (3 x 20 mL), the organic phase washed with water (2 x 20 mL). The combined aqueous phases were evaporated on a rotary evaporator.
• the resulting white-yellowish residue (3.63 g) consists of the sodium salt of thiosulphuric acid S- [2- (benzofuran-3-yl) ethyl] ester ("Bunte salt”) contains an undefined residual amount of water. The subsequent conversion to the thiol was carried out without further purification.
• diastereomer 3 hemicitrate
• Nonpolar diastereomer 4 hemicitrate
• Nonpolar diastereomer 5 citrate
• Polarer diastereomer 6 tartrate
• One of 2 diastereomers 7 triflate
• the cyclohexane derivatives of the general formula I were investigated in a receptor binding assay with 3 H-nociceptin / orphanin FQ with membranes from recombinant CHO-ORL1 cells.
• This test system was tested according to the Ardati et al. (Mol. Pharmacol., 51, 1997, pp. 816-824 ) method.
• the concentration of 3 H-nociceptin / orphanin FQ was 0.5 nM in these experiments.
• the binding assays were carried out with 20 ⁇ g membrane protein per 200 ⁇ l batch in 50 mM Hepes, pH 7.4, 10 mM M 9 Cl 2 and 1 mM EDTA.
• Binding to the ORL1 receptor was determined using 1 mg each of WGA-SPA beads (Amersham-Pharmacia, Freiburg), incubation of the mixture for one hour at RT and subsequent measurement in the scintillation counter Trilux (Wallac, Finland).
• the receptor affinity for the human ⁇ -opiate receptor was determined in a homogeneous batch in microtiter plates. For this purpose, dilution series of each substituted substituted spirocyclic cyclohexane derivative to be tested with a receptor membrane preparation (15-40 micrograms of protein per 250 ul incubation mixture) of CHO-K1 cells expressing the human ⁇ -opiate receptor (RB-HOM receptor membrane preparation NEN, Zaventem, Belgium) in the presence of 1 nmol / l of the radioactive ligand [ 3 H] -aloxone (NET719, NEN, Zaventem, Belgium) and 1 mg of WGA-SPA beads (Wheat germ agglutinin SPA beads of Amersham / Pharmacia, Freiburg, Germany) in a total volume of 250 ⁇ l for 90 minutes at room temperature.
• a receptor membrane preparation 15-40 micrograms of protein per 250 ul incubation mixture
• CHO-K1 cells expressing the human ⁇ -opiate receptor RB
• the incubation buffer used was 50 mmol / l Tris-HCl supplemented with 0.05% by weight sodium azide and with 0.06% by weight bovine serum albumin. To determine the unspecific binding an additional 25 .mu.mol / l naloxone was added. After the ninety-minute incubation period, the microtiter plates were centrifuged for 20 minutes at 1000 g and the radioactivity in a ⁇ -counter (Microbeta-Trilux, PerkinElmer Wallac, Freiburg, Germany) measured.
• the percentage displacement of the radioactive ligand from its binding to the human ⁇ -opiate receptor at a concentration of the test substances of 1 .mu.mol / l was determined and expressed as a percentage inhibition (% inhibition) of the specific binding.
• IC 50 inhibitory concentrations were calculated, which cause a 50% displacement of the radioactive ligand.
• Ki values were obtained for the test substances.
• the analgesic efficacy study was modified in phenyl-quinone-induced writhing in the mouse (modified after IC Hendershot and J. Forsaith (1959) J. Pharmacol. Exp. Ther. 125, 237-240 ) carried out.
• male NMRI mice weighing 25 to 30 g were used.
• Ten minutes after the intravenous administration of the test substances groups of 10 animals per substance dose received 0.3 ml / mouse of a 0.02% strength aqueous solution of phenylquinone (phenylbenzoquinone, Sigma, Deisenhofen, preparation of the solution with the addition of 5% ethanol and storage in a water bath at 45 ° C) intraperitoneally.
• the ED 50 values with 95% confidence interval of the writhing reaction were calculated from the dose-dependent decrease of the writhing reactions in comparison to parallel examined phenylquinone control groups by regression analysis (evaluation program Martens EDV Service, Eckental).
• mice were individually placed in a test cage and the tail base exposed to the focused heat beam of an electric lamp (tail-flick type 50/08 / 1.bc, Labtec, Dr. Hess).
• the lamp intensity was adjusted so that the time from switching on the lamp to the sudden winceing of the tail (pain latency) in untreated mice was 3 to 5 seconds.
• the mice were pretested twice within five minutes and the mean value of these measurements was calculated as the pretest mean value.
• the solutions of the compound of general formula I according to the invention and the comparative solutions were then administered intravenously.
• the pain measurement was carried out in each case 10, 20, 40 and 60 minutes after the intravenous application.
• the analgesic effect was determined as an increase in pain latency (% of the maximum possible antinociceptive effect) according to the following formula: T 1 - T 0 / T 2 - T 0 ⁇ 100
• the time T 0 is the latency before the application
• the time T 1 is the latency after the application of the active substance combination
• the time T 2 is the maximum exposure duration (12 seconds).
• Table 1 ⁇ / b> Example no.
• Tail flick Mouse, iv) ED 50 [mg / kg] or % Inhibition (dose [mg / kg]) 1 0.3 0.6 0.0035 2 310 3 0.6 1.3 0.0182 (ip) 4 3.7 3.1 6 53% 7 76% 8th 80% 89% (10) 9 0.26 0.36 94% (1) 10 3.4 4.5 11 2.9 4.4 12 2.4 2.2 67% (0.1) 13 5.8 2.0 0.0033 0.02 14 1.2 12.0
• Example 54 Parenteral solution of a spirocyclic cyclohexane derivative of the invention

Landscapes

• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Pain & Pain Management (AREA)
• Hematology (AREA)
• Diabetes (AREA)
• Addiction (AREA)
• Psychiatry (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Obesity (AREA)
• Urology & Nephrology (AREA)
• Anesthesiology (AREA)
• Physical Education & Sports Medicine (AREA)
• Endocrinology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Reproductive Health (AREA)
• Psychology (AREA)
• Hospice & Palliative Care (AREA)
• Child & Adolescent Psychology (AREA)
• Nutrition Science (AREA)
• Dermatology (AREA)
• Rheumatology (AREA)
• Gynecology & Obstetrics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (6)

Applications Claiming Priority (3)

Related Child Applications (3)

Publications (2)

Family

ID=32185555

Family Applications (4)

Family Applications After (3)

Country Status (27)

Cited By (1)

Families Citing this family (103)

Family Cites Families (26)

• 2002
  • 2002-11-11 DE DE2002152667 patent/DE10252667A1/de not_active Ceased
• 2003
  • 2003-11-05 EP EP20030810963 patent/EP1560835B1/de not_active Expired - Lifetime
  • 2003-11-05 DK DK08022243T patent/DK2062898T3/da active
  • 2003-11-05 ES ES09009500.1T patent/ES2587013T3/es not_active Expired - Lifetime
  • 2003-11-05 EP EP09009500.1A patent/EP2116544B1/de not_active Expired - Lifetime
  • 2003-11-05 BR BRPI0315296A patent/BRPI0315296B8/pt not_active IP Right Cessation
  • 2003-11-05 PL PL376793A patent/PL215227B1/pl unknown
  • 2003-11-05 ES ES08022243T patent/ES2438269T3/es not_active Expired - Lifetime
  • 2003-11-05 KR KR1020097025244A patent/KR101075817B1/ko not_active Expired - Fee Related
  • 2003-11-05 AU AU2003296563A patent/AU2003296563B2/en not_active Ceased
  • 2003-11-05 PT PT03810963T patent/PT1560835E/pt unknown
  • 2003-11-05 MX MXPA05004959A patent/MXPA05004959A/es active IP Right Grant
  • 2003-11-05 CN CN2009102104076A patent/CN101693714B/zh not_active Expired - Fee Related
  • 2003-11-05 ES ES10005484.0T patent/ES2587185T3/es not_active Expired - Lifetime
  • 2003-11-05 DK DK03810963T patent/DK1560835T3/da active
  • 2003-11-05 WO PCT/EP2003/012305 patent/WO2004043967A1/de not_active Ceased
  • 2003-11-05 JP JP2004550924A patent/JP4728645B2/ja not_active Expired - Fee Related
  • 2003-11-05 CA CA2505555A patent/CA2505555C/en not_active Expired - Fee Related
  • 2003-11-05 BR BRPI0318811A patent/BRPI0318811B8/pt not_active IP Right Cessation
  • 2003-11-05 PL PL390420A patent/PL217804B1/pl unknown
  • 2003-11-05 ES ES03810963T patent/ES2333956T3/es not_active Expired - Lifetime
  • 2003-11-05 SI SI200331703T patent/SI1560835T1/sl unknown
  • 2003-11-05 PT PT08022243T patent/PT2062898E/pt unknown
  • 2003-11-05 SI SI200332314T patent/SI2062898T1/sl unknown
  • 2003-11-05 CN CN200380108583A patent/CN100577664C/zh not_active Expired - Fee Related
  • 2003-11-05 KR KR1020057008319A patent/KR101075810B1/ko not_active Expired - Fee Related
  • 2003-11-05 DE DE50311874T patent/DE50311874D1/de not_active Expired - Lifetime
  • 2003-11-05 NZ NZ540575A patent/NZ540575A/en not_active IP Right Cessation
  • 2003-11-05 AT AT03810963T patent/ATE441650T1/de active
  • 2003-11-05 EP EP20080022243 patent/EP2062898B1/de not_active Expired - Lifetime
  • 2003-11-05 EP EP10005484.0A patent/EP2233487B1/de not_active Expired - Lifetime
  • 2003-11-05 RU RU2005118403A patent/RU2354656C2/ru active
  • 2003-11-06 PE PE2003001126A patent/PE20040830A1/es active IP Right Grant
  • 2003-11-11 AR ARP030104135 patent/AR041932A1/es active IP Right Grant
• 2005
  • 2005-05-09 IL IL168473A patent/IL168473A/en active IP Right Grant
  • 2005-05-10 EC ECSP055786 patent/ECSP055786A/es unknown
  • 2005-05-10 CO CO05044351A patent/CO5580765A2/es unknown
  • 2005-05-11 US US11/126,139 patent/US7547707B2/en not_active Expired - Lifetime
  • 2005-06-07 NO NO20052761A patent/NO331818B1/no not_active IP Right Cessation
  • 2005-06-09 ZA ZA200504725A patent/ZA200504725B/en unknown
• 2009
  • 2009-02-17 US US12/372,340 patent/US8053576B2/en not_active Expired - Lifetime
  • 2009-02-17 US US12/372,358 patent/US7799931B2/en not_active Expired - Lifetime
  • 2009-08-14 JP JP2009187933A patent/JP2010006815A/ja not_active Withdrawn
  • 2009-08-28 AR ARP090103322 patent/AR074529A2/es active IP Right Grant
  • 2009-09-24 NO NO20093060A patent/NO331776B1/no not_active IP Right Cessation
  • 2009-11-30 CY CY20091101250T patent/CY1110558T1/el unknown
• 2010
  • 2010-01-05 IL IL203141A patent/IL203141A/en active IP Right Grant
  • 2010-01-20 AU AU2010200219A patent/AU2010200219B2/en not_active Ceased
  • 2010-04-19 US US12/762,719 patent/US7951948B2/en not_active Expired - Lifetime
  • 2010-09-06 JP JP2010199044A patent/JP5442565B2/ja not_active Expired - Fee Related
  • 2010-09-06 JP JP2010199045A patent/JP5539821B2/ja not_active Expired - Fee Related
• 2011
  • 2011-09-02 US US13/225,008 patent/US9120797B2/en not_active Expired - Lifetime
• 2013
  • 2013-11-04 CY CY20131100973T patent/CY1114616T1/el unknown
• 2015
  • 2015-07-21 US US14/804,847 patent/US9862719B2/en not_active Expired - Fee Related

Also Published As

Similar Documents

Legal Events